Background DNA methylation is thought to be an important determinant of human phenotypic variation, but its inherent cell type specificity has impeded progress on this question. At exceptional genomic regions, interindividual variation in DNA methylation occurs systemically. Like genetic variants, systemic interindividual epigenetic variants are stable, can influence phenotype, and can be assessed in any easily biopsiable DNA sample. We describe an unbiased screen for human genomic regions at which interindividual variation in DNA methylation is not tissue-specific. Results For each of 10 donors from the NIH Genotype-Tissue Expression (GTEx) program, CpG methylation is measured by deep whole-genome bisulfite sequencing of genomic DNA from tissues representing the three germ layer lineages: thyroid (endoderm), heart (mesoderm), and brain (ectoderm). We develop a computational algorithm to identify genomic regions at which interindividual variation in DNA methylation is consistent across all three lineages. This approach identifies 9926 correlated regions of systemic interindividual variation (CoRSIVs). These regions, comprising just 0.1% of the human genome, are inter-correlated over long genomic distances, associated with transposable elements and subtelomeric regions, conserved across diverse human ethnic groups, sensitive to periconceptional environment, and associated with genes implicated in a broad range of human disorders and phenotypes. CoRSIV methylation in one tissue can predict expression of associated genes in other tissues. Conclusions In addition to charting a previously unexplored molecular level of human individuality, this atlas of human CoRSIVs provides a resource for future population-based investigations into how interindividual epigenetic variation modulates risk of disease. Electronic supplementary material The online version of this article (10.1186/s13059-019-1708-1) contains supplementary material, which is available to authorized users.

Chronic stressors promote metabolic disturbances, including obesity and metabolic syndrome. Ghrelin, a peptide that promotes appetite and the accumulation of adipose tissue, is also secreted in response to stressors to protect the brain and peripheral tissues from the effects of these stressors. Here we demonstrate that elevated ghrelin levels produced by chronic exposure to social stress are associated with increased caloric intake and body weight gain in male C57BL mice. In contrast, stressed mice lacking ghrelin receptors (GHSR KO mice) or C57BL mice receiving chronic intracerebroventricular delivery of the ghrelin receptor antagonist [d-Lys(3)]-GHRP-6 show attenuated weight gain and feeding responses under the same social stress paradigm. Interestingly, stressed GHSR KO mice showed depleted sc and intrascapular brown fat depots, whereas stressed young wild-type mice did not. In old wild-type mice, chronic social defeat increased visceral and intrascapular brown fat depots in association with increases in obesity markers like hyperleptinemia and hyperinsulinemia along with increased hypothalamic expression of neuropeptide Y and Agouti related peptide. Importantly, the elevated expression of these peptides persisted least for 2 weeks after cessation of the stressor regimen. In contrast, old GHSR KO mice did not show these alterations after chronic social defeat. These results suggest that ghrelin plays an important role in the metabolic adaptations necessary to meet the energetic demands posed by stressors, but chronic exposure to stress-induced ghrelin elevations ultimately could lead to long lasting metabolic dysfunctions.

This study examined stimulus class membership established via stimulus-reinforcer relations. Mentally retarded subjects learned conditional discriminations with four two-member sets of visual stimuli (A, B, C, and D). On arbitrary-matching trials, they selected comparison stimuli B1 and B2 conditionally upon samples A1 and A2, respectively, and C1 and C2 conditionally upon B1 and B2, respectively. On identity-matching trials, they selected all stimuli as comparisons conditionally upon identical stimuli as samples. Throughout training, correct selections of A1, B1, C1, and D1 were followed by one reinforcer, R1, and those of A2, B2, C2, and D2 were followed by another, R2. Subsequent tests documented the formation of two four-member stimulus classes, A1-B1-C1-D1 and A2-B2-C2-D2. The class membership of the A, B, and C stimuli could have been based on equivalence relations that resulted from the arbitrary-matching training. D1 and D2 had never appeared on arbitrary-matching trials, however. Their class membership must have been based on relations with R1 and R2, respectively. Results thus confirm a previous finding that stimulus classes can be expanded via stimulus-reinforcer relations. They also define more precisely the potential nature of those classes and the conditions under which class membership can be established.

In an arbitrary matching-to-sample procedure, two mentally retarded subjects learned conditional discriminations with two sets of stimuli. Each set included a spoken name (NI or N2), an object (01 or 02), and a printed symbol (Si or S2). One subject selected conditionally (a) 01 upon NI, and 02 upon N2, and (b) Si upon 01, and S2 upon 02. The other subject selected conditionally (a) Si upon NI, and S2 upon N2, and (b) 01 upon Si, and 02 upon S2. For both subjects, selections of 01 and Si produced one type of food, Fl; selections of 02 and S2 produced a different type of food, F2. Both subjects also learned identity-matching performances, selecting 01, 02, Si, S2, Fl, and F2 conditionally upon those stimuli as samples; Fl followed selections of 01, Si, and Fl; F2 followed selections of 02, S2, and F2. Matching performances consistent with stimulus class formation involving the names, objects, symbols, and foods were demonstrated on probe trials, even though these performances had not been taught explicitly. Next, new objects, Xi and X2, were presented on identity-matching trials, producing Fl and F2, respectively. Without further training, Xi was selected conditionally upon Ni, Si, and 01, and X2 was selected upon N2, S2, and 02. When the contingencies were changed so that selections of Xi and X2 were now followed by F2 and Fl, respectively, X2 was selected conditionally upon Ni, Si, and 01, and Xi was selected upon N2, S2, and 02. Class membership of Xi and X2 had apparently changed. This study provides evidence that reinforcers may become members of stimulus classes, and that new stimuli may become class members through relations with reinforcers.